June 2, 2003

Innovative, Multicenter Study of Schizophrenia Will Follow Disease Traits in Hunt for Genetic Causes

$20-million, 7-Center Grant headed by University of California, San Diego

Specific information processing abnormalities and brain-related circuit dysfunction in schizophrenia patients may be the keys to finding the genetic basis of this puzzling, devastating mental illness that affects more than two million Americans and one percent of the world's population.

Scientists believe multiple genes cause schizophrenia, but specifically, the genetic basis of this disorder remains somewhat of a mystery. Research has pointed to several chromosomes that harbor likely disease-causing genes, but the search has been unsuccessful for the exact genetic code that causes this devastating, but elusive disorder.

Now, with a $20-million, five-year grant from the National Institute of Mental Health, seven academic research centers in the U.S., led by the University of California, San Diego (UCSD) School of Medicine, are taking a different approach to uncover the genetic causes of schizophrenia. Rather than starting with the broadly defined disorder itself, scientists are beginning with specific physiological markers, or traits, that are characteristic of schizophrenia in both patients and some clinically unaffected, normal family members. These physiological markers caused by defects in brain circuits will then be used to identify the complex genetic abnormalities that cause them.

David Braff, M.D.

"I believe our research is an important step in furthering our understanding of schizophrenia and then identifying the critical, genetically mediated brain dysfunctions that contribute to the disease," said David Braff, M.D., UCSD professor of psychiatry and director of the seven-center Consortium on the Genetics of Schizophrenia (COGS). "Instead of exploring the genetics of schizophrenia, we're identifying the genetics of different neurological deficits that occur in schizophrenia patients. "

He added that the main research hypothesis is based on the tenets of molecular biology. "If there are several different genetic abnormalities associated with schizophrenia, then each of them would cause a change in a specific protein. We believe that the series of protein changes in this disease is reflected by corresponding discrete functional abnormalities, such as disorganized thought processes," Braff said.

This strategy has been used for gene discovery in other complex medical illnesses. For example, in a form of colon cancer, researchers were able to identify a gene that causes multiple polyp formation, which leads to the cancer, rather than finding a gene for the cancer, itself.

At least six specific schizophrenia traits, called endophenotypes, will be studied in more than 2,000 individuals. UCSD, which is leading the project, will be joined by researchers at Harvard, Mt. Sinai School of Medicine, UCLA, University of Colorado Health Sciences Center, University of Pennsylvania and University of Washington, Seattle. Key to the studies will be the testing of individuals with schizophrenia and their clinically unaffected family members. These family members may have the same liability genes and associated traits, but are normal and don't show clinical signs of the disease. Specifically, the researchers will study cognitive dysfunction and abnormalities in perception and information processing experienced by schizophrenia patients. (See below for descriptions of tests.)

For example, schizophrenia patients, family members and "normal" individuals will be tested for deficits in the ability to inhibit, or "gate" irrelevant stimuli. People are constantly bombarded with a multitude of external and internal stimuli, and most individuals are able to select those stimuli that are most relevant to current activities and goals, while screening out or gating irrelevant stimuli. Schizophrenia patients are unable to filter the trivial from essential information and stimuli in everyday sensory input. They, therefore, have troubles navigating in everyday life activities because they are easily distracted, confused, and they become disorganized.

The disordered thinking that is characteristic of schizophrenia may be manifested in some of the more visible features of the disease, such as disorganization of speech and behavior with associated disabilities in work and social relationships.

"Ultimately, the COGS study will lead to a better understanding of the genetic abnormalities associated with these cognitive and information processing dysfunctions in schizophrenia patients," Braff said. "On a longer term basis, this functional genetics approach may lead to a new era of genetically informed treatment options. Thus, medications will be aimed at reversing genetically mediated brain dysfunctions and restoring schizophrenia patients to better levels of social and work function as their symptoms are alleviated."

The term "schizophrenia" was first coined by Eugen Bleuler in 1911. It comes from the Greek roots schizo (split) and phrene (mind) to describe the fragmented thinking of people with the disorder. Although his term was not meant to convey the idea of split or multiple personality, this interpretation has been a common mistake over the decades.

Individuals who are interested in participating in the Consortium on the Genetics of Schizophrenia program should call 619-543-7201, or email szresearch@ucsd.edu.

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Each of the following six endophenotypes is abnormal in schizophrenia patients and their normal family members. These abnormalities reflect genetic coding dysfunctions. Fortunately, unaffected family members can compensate for or do not have the full range of deficits of the patients, perhaps because they have less "loading" of disease genes and/or fewer non-genetic risk factors, such as birth complications.

Endophenotype Tests (deficits seen in schizophrenia patients and their normal family members):

  1. P50 Suppression. Sensors placed on the scalp measure brain waves called P50 that are elicited by external stimuli. In this case, the individual hears one click that is rapidly followed (typically 500 milliseconds or one-half second later) by a second click. The P50 brain wave in normal subjects responds to the first click but exhibits an 80 percent smaller response to the second click. Individuals with schizophrenia respond to the same degree to both clicks, reflecting a failure of normal "gating".
  2. Prepulse Inhibition (PPI) of the Startle Response. Normally, a powerful and sudden sensory stimulus, such as a burst of noise, elicits a whole body startle response, which is measured by small electrodes placed on facial muscles. This measures the eye-blink component of the startle response. When the startling stimulus is preceded by approximately 100 milliseconds by a weak pre-stimulus, the startle response is inhibited in normal persons, but not in schizophrenia patients. This is another example of a failure to normally "gate" environmental stimuli.
  3. Antisaccade Eye Movement. A test of eye movement, called saccade control, measures the rapid redirection of gaze to locations of interest. Individuals with schizophrenia are unable to avoid looking at a visual cue they've been told to ignore. This is a neuronal circuit based failure of normal information processing and the ability to avoid distraction.
  4. Continuous Performance Test. This neurocognitive test measures sustained, focused attention. The subject is presented with visual stimuli and asked to press a button each time that a target stimulus appears. Deficits in detection within a continuous series of briefly presented stimuli have been found in individuals with schizophrenia.
  5. Verbal Memory. Previous studies have shown verbal memory to be one of the most impaired neurocognitive functions in schizophrenia, with the primary deficit in the encoding and organization of information. Subjects are given a list-learning memory test, which requires recalling five trials of a list of 16 items.
  6. Working Memory. Another test where schizophrenia patients and their clinically normal family members consistently show deficits is working memory. This can refer to transient online storage of information in which participants need to keep information in mind for a short period of time, or to the storage, manipulation and retrieval of information (sometimes called "executive-functioning working memory"). In this test, subjects are presented with clusters of intermixed numbers and letters. They are then asked to reorder the stimuli so that the numbers are presented in ascending order and the letters in alphabetical order.

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